JPH03275681A - 3-phenylcoumarin-7-yloxy acetate derivative, production thereof and use same derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> to R<3> and R<1>' to R<5>' are H, halogen, lower alkyl or lower alkoxy). USE:Used as an aldose reductase inhibitor. Said compound is useful as remedy of diabetic complication having high safety. PREPARATION:7-hydroxy-3-phenylcoumarin derivative expressed by formula II is reacted with halogenoacetic acid ester (e.g. ethyl bromoacetate) and hydrolyzed to afford the aimed compound.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel 3-phenylcoumarin-7-yloxyacetic acid derivative or a salt thereof useful as a pharmaceutical.

[Conventional technology]

The number of diabetic patients has increased dramatically in recent years due to the Westernization of dietary habits, and there is an urgent need for countermeasures to treat the disease. Insulin and hypoglycemic agents have traditionally been widely used as diabetes treatment drugs, but diabetes is a disease that involves not only abnormal glucose metabolism but also various complications, so these drugs alone are not sufficient. .

Accumulation of intracellular sorbitol via the polyol pathway, which is a glucose metabolic pathway, is attracting attention as a cause of various complications of diabetes such as retinopathy, cataracts, neuropathy, and nephropathy. The enzyme that catalyzes the conversion between aldose and polyol, which is the first step in this polyol pathway, is called aldose reductase, and this enzyme is considered to be the rate-limiting enzyme in the polyol pathway. By inhibiting this aldose reductase and reducing the production and accumulation of sorbitol,
It is possible to prevent and treat diabetic complications such as those mentioned above (
R.G., Jurgilminsch et al.: New England
Journal of Medicine (NewEng, J.
Med, ), volume 308, pages 119-125 (198
3): J, H.

Kinoshita etc. Metabolism (Metabolism)
m) + 28 volumes (1).

(pp. 462-469 (1979)) [Problems to be Solved by the Invention] An object of the present invention is to provide a drug useful for inhibiting the above-mentioned aldose reductase.

[Means to solve the problem]

The present invention specifically relates to the general formula (I) (wherein al, R1, R3 and R1/, R11
, R3/R4/ , Rjl/ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group)
The compound of the present invention, which is a 3-phenylcoumarin-7-yloxyacetic acid derivative or a salt thereof, and is an aldose reductase inhibitor containing these as an active ingredient can be produced as follows.

That is, general formula (II) is a Perkin-Oglialoro reaction (Perkin-Oglialoro R
(N,
R.

Krishnas-wary, et al, + I
ndian, J, Cheap,, 4°120,
(1966). ] Reaction formula (a) (However, in the formula, R', l?", R3 and R", Rg/
, R3/.

It is obtained by reacting a 7-hydroxy-3-phenylcoumarin derivative represented by R4/ , QSI has the same meaning as in the above general formula (I) with a halogenoacetic acid ester, and then hydrolyzing it. In this specification, “
The word "lower" means that the group to which this word is attached has 6 carbon atoms.
4 or less, preferably 4 or less.

In order to react the compound of the general formula (FF) which is a raw material for the compound of the present invention with the halogen acetate to form the compound of the general formula (1), a conventional method can be used, for example, in acetone. , potassium carbonate and ethyl bromoacetate to obtain the ester of the compound of general formula (I).

The resulting ester of the compound of general formula (I) is hydrolyzed in acetic acid with water or mineral acid, or hydrolyzed with basicity and adjusted to around pH 4 with mineral acid to form the free acid, that is, the compound of general formula (1). ) becomes the acid of the compound, which is then adjusted to pH using an inorganic base.
By adjusting it to around 9, it becomes an inorganic salt of the compound of general formula (I).

All of these can be isolated by known methods such as concentration, drying and other methods, and purified by recrystallization. Mineral acids used here include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc., and inorganic bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, etc. Alkali hydroxide, sodium carbonate,
Examples include alkali carbonates such as potassium carbonate and ammonium carbonate, and alkali bicarbonates such as sodium bicarbonate, potassium bicarbonate, and ammonium bicarbonate.

The aldose reductase inhibitor containing the compound represented by the general formula (1) or a salt thereof as an active ingredient can be prepared into tablets, capsules, injections, powders, or tablets in a conventional manner using a commonly used carrier.

It may also be used in granules, suppositories, eye drops, etc.

〔Example〕

Next, the compound of the present invention, its production method, and aldose reductase inhibitory effect will be explained in detail with reference to Examples, but the present invention is not limited to the following Examples. Note that the melting points of the products in each example are all uncorrected.

Reference example 1 β-resorcyl aldehyde 5.0 g (0,036 mol) and sodium phenylacetate 5.6 g (0,03
6 mol) in 30 ml of acetic anhydride and heated under reflux for 9 hours. After cooling, water is added, and the precipitated crystals are taken out and dried. Then, after recrystallizing ethanol/acetone, 3.0 g of the obtained 7-acetyl-3-phenylcoumarin was diluted with acetic acid 4.
9 ml of concentrated hydrochloric acid was added to a mixed solution of 10 ml of concentrated hydrochloric acid, and the mixture was heated under reflux for 2 hours. After drying, recrystallization with acetone/benzene yields 2.1 g of 7-hydroxy-3-phenylcoumarin.

Yield 77.7%.

mp 209-210°C, Compound 1 in [Table 1] Reference Example 2 Compounds 2 to 12 in Table 1 are obtained in the same manner as in Reference Example 1. Table 1 shows the physical property values of the general formula (It) thus obtained.

Example 1 2.0 g of 7-hydroxy-3-phenylcoumarin (0,
008 mol), ethyl bromoacetate 1.4 g (0,008 mol)
mol), 0.1 g of potassium iodide and 10 g of anhydrous potassium carbonate in 50 ml of acetone! Add to the mixture, stirring, 4
Heat to reflux for an hour. After cooling, insoluble materials are removed, the solvent is distilled off, and the resulting residue is dissolved in ether. This ether solution is washed successively with water, a 5% by weight aqueous sodium hydroxide solution, and water, and the ether layer is dried over anhydrous sodium sulfate. The solvent was distilled off, and the resulting residue was recrystallized from acetone/hexane to obtain 1.95 g (yield: 71.6%) of ethyl 3-phenylcoumarin-7-yloxyacetate.

Add 1.95 g of the above ester to 30 ml of ethanol and 5
Weight% sodium hydroxide aqueous solution 15mj! and heated under reflux for 30 minutes. After cooling, remove the insoluble matter,
Make the furnace liquid acidic with hydrochloric acid. Collect the precipitated crystals. After drying, recrystallization with acetone yields 3-phenylcoumarin-7.
1.45 g of -yloxyacetic acid are obtained. Yield: 80.
0%, mp212-214°C, Compound 1 in [Table 2]
Example 2 Compounds 2 to 12 in Table 2 are obtained in the same manner as in Example 1. Table 2 shows the physical properties of the derivative of the compound of general formula (I) thus obtained.

Further, the aldose reductase inhibitory activity of the compound of general formula (I) is IC. It is also listed in Table 2.

<Aldose reductase inhibitory effect> Seven-week-old male Wistar rats were sacrificed under ether anesthesia, and the crystalline lenses were immediately removed.

The crystalline lens was prepared using 1.0mM 2-mercaptoethanol and 1.0mM 2-mercaptoethanol. OmM NADP (oxidized nicotinam)
ideadenine dinucleotide p
Homogenization was performed in a 100 mM sodium-potassium-phosphate buffer (pH 6, 8) containing phosphate. Then, centrifugation at 12.00 rpm for 15 minutes,
The supernatant was used as a sample for aldose reductase activity measurement.

All of the above operations were performed at 4°C and the specimens were stored at -80°C.

The activity of aldose reductase can be measured using KADOR.
) et al. [Biophysical Chemist
ry8 (197B) 81-85]. That is, 0.1mM NADPH (reduced n1cotinaside adenine) as a coenzyme.
dinucleotide phosphate)
To 970 μl of 100 mM sodium-potassium-phosphate buffer (pH 6,2) containing 2.9 mM DL-glyceraldehyde as a substrate, 10 μl of various concentration solutions of the compound of the present invention were added, and then 20 μl of the above specimen was added, and the mixture was incubated at 25°C. The reaction was carried out. As a control, only the substrate was lacking, and the decrease in absorbance at 340 nm was measured by 20
Measured for 0 seconds. Further, instead of adding the sample solution, only the solvent was added, and the reaction and measurement were performed in the same manner as above, and the result was used as a control value. The absorbance was measured using UV-260 (manufactured by Shimadzu Corporation). As a result, the inhibitory activity against aldose reductase was as shown in Table 2.
Molar concentration at 0% inhibition 0.18-5.5 (I x 10
-'M) was observed.

(Left below) <Acute Toxicity> Acute toxicity test was conducted by oral administration of the compounds of general formula (1) obtained from each side above using DDY mice (body weight 23-25 g). No deaths were observed even after oral administration.

〔Effect of the invention〕

As is clear from the above results, the novel 3-phenylcoumarin-7-yloxyacetic acid derivative of the present invention has an aldose reductase inhibitory effect and is useful as a highly safe drug for treating diabetic complications.

Claims (3)

[Claims] (1) General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, in the formula, R^1, R^2, R^3, R^1', R
3-phenylcoumarin-7-yloxyacetic acid derivative or its salt. (2) General formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (However, in the formula, R^1, R^2, R^3 and R^1', R
^2', R^3', R^4', R^5' are the general formulas (
7-hydroxy-3-phenylcoumarin derivative represented by the above general formula (I) is reacted with a halogenoacetic acid ester, and then hydrolyzed.
- A method for producing a phenylcoumarin-7-yloxyacetic acid derivative or a salt thereof. (3) An aldose reductase inhibitor containing a 3-phenylcoumarin-7-yloxyacetic acid derivative represented by the above general formula (I) or a salt thereof as an active ingredient.